Truncations of Titin Causing Dilated Cardiomyopathy

Summary

Dr Christine Seidman and coworkers analyzed TTN, the gene encoding the sarcomeric protein titin, in 312 subjects with DCM , 231 individuals with HCM and in 249 controls using next-generation or dideoxy sequencing. Also clinical characteristics of the patients and cosegregation in families were assessed.

72 unique mutations, which altered full-length titin, were identified. They comprised 25 nonsense, 23 frameshift, 23 splicing mutations and 1 large tandem insertion. TTN mutations were found in 54/203 (27%) DCM patients, in 3/231 (1%) HCM patients and in 7/249 (3%) controls (p=9x10 -14). Combined lod score for the cosegregation of TTN mutation with DCM was 11.1 and thus the mutations were considered as disease causing. The penetrance of the mutations was high (>95%) in subjects aged over 40 years. Mutations in the A-band of titin were overrepresented among DCM-patients. In the subjects with HCM, three TTN truncating variants were found. The rates of cardiac outcomes were similar in individuals with and without TTN mutations but adverse events occurred earlier in male mutation carriers than in female carriers (P=4x 10-5).
The authors conclude that mutations which disrupt the structure of full-length titin might cause DCM by several mechanisms. Some of the truncated titin molecules may be degraded. Decreased titin levels might reduce sarcomere formation and cause cardiac dysfunction. On the other hand, some of the carboxy-terminal truncated titin molecules are integrated into the sarcomere and cause recessive, early-onset skeletal and cardiac myopathy instead of dominant DCM. The skewed mutation distribution in subjects with DCM as compared to individuals without the disease suggests that truncated titin molecules in DCM patients are integrated into the sarcomere and might cause DCM by a dominant negative mechanism. If truncated proteins were incorporated into the sarcomere, the truncated titin proteins would not contain those amino acid residues that are needed to anchor titin to the middle of the sarcomere. The authors suggest that the loss of interactions, which mediate sensing and modulating sarcomeric force might lead to DCM.

The investigators conclude that TTN mutations are the most common known genetic cause of DCM and suggest incorporation of next-generation sequencing analyses of TTN into clinical genetic screens.

Comments

The molecular etiology of DCM is heterogeneous. The multitude of genes associated with DCM has hampered clinical genetic testing. The findings of this study form a basis for further studies concerning myocyte signalling. Including TTN into clinical genetic testing screens probably greatly increases the yield of genetic testing among DCM patients.